PROJECT III: ROLE OF 17?-HYDROXYSTEROID DEHYDROGENASE IN THE HYPERTENSION OF PCOS. SUMMARY Polycystic Ovary Syndrome (PCOS) is characterized by increases in plasma androgens and/or hirsutism, irregular menstrual periods, ovarian cystic morphology and infertility. Although the etiology of PCOS is unknown, one theory is that PCOS may be developmentally programmed due to exposure to prenatal androgens. PCOS is one of the most common female endocrine disorders, affecting 5 to 26% of women of reproductive age depending on ethnicity and lifestyle. Recent attention in women with PCOS in the US has focused on several metabolic derangements such as obesity, insulin resistance and hypertension. In the US the prevalence of obesity in PCOS women is up to 80%. Obesity plays a major role in the clinical manifestations of the syndrome, since weight loss is associated with improved fertility and reductions in metabolic derangements in PCOS patients. Several lines of evidence indicate that there is a positive relationship between circulating levels of androgens, obesity, insulin resistance and blood pressure (BP) in women with PCOS. Whether and how increases in circulating androgens cause obesity, insulin resistance and hypertension in PCOS women remains poorly understood and is the main focus of this proposal. We have established an animal model of PCOS in female rats that mimics many of the metabolic and cardiovascular abnormalities of women with PCOS. Implantation of dihydrotestosterone (DHT) pellets in female rats causes an increase in food intake, subcutaneous adipose tissue, insulin resistance, obesity, and elevated BP, as observed in PCOS women. In this proposal we will test the hypothesis that in PCOS, increased plasma androgens via the androgen receptor cause an increase in food intake leading to obesity that includes an increase in subcutaneous adipose tissue, and insulin resistance. The combination of increased circulating androgens, obesity and insulin resistance activate adipose 17?-HSD, resulting in increased adipose androgen synthesis that further increases circulating androgen levels setting up a vicious cycle. Increased circulating androgens lead to subsequent activation of the intrarenal renin angiotensin system and elevated blood pressure. This hypothesis will be tested using an integrative physiological approach using whole animal, cellular, molecular and imaging methods in the following specific aims: 1) to test the hypothesis that increased circulating androgens via activation of the androgen receptor promotes obesity with an increase in subcutaneous adipose tissue and insulin resistance in PCOS; 2) to test the hypothesis that increases in subcutaneous adipose tissue and insulin resistance lead to activation of 17?-HSD in the subcutaneous adipose tissue, thus further increasing circulating levels of androgens in PCOS; 3) to test the hypothesis that increased circulating androgens activate the intrarenal renin-angiotensin system (RAS), shifting the pressure-natriuresis curve to the right, leading to increases in blood pressure in PCOS; 4) to test the hypothesis that either elevated circulating androgens or activation of the RAS by androgens leads to insulin resistance in PCOS independently of obesity. This novel and clinically relevant proposal will elucidate potential mechanisms by which androgens regulate blood pressure, promote obesity and insulin resistance in women with PCOS, determine the pathophysiological interactions between these cardiovascular risk factors and will pave the way to identify novel and improved therapeutic tools to treat the clinical manifestations associated with hyperandrogenism in PCOS women.